This project addresses the cellular mechanisms underlying the dual actions of estrogen in women with Alzheimer's Disease, i.e., the improvement of the cognitive deficits and the reduced incidence of AD in women with estrogen replacement therapy. These effects of estrogen suggest that estrogen or some equine estrogen constituent acts as a cognitive enhancer and/oras a neuroprotective agent. These hypothesis will be tested in in vitro models of synaptic plasticity and neurodegeneration. Long-term potentiation (LTP) is widely considered to represent a cellular mechanism for information storage and compounds modulating LTP have been found to modulate learning and memory processes. LTP induction and expression are critically dependent on 2 classes of inotropic receptors, the NMDA and the AMPA receptors, respectively. Specific Aims 1 and 2 will therefore be directed at determining the effects of acute and chronic estrogen treatment of hippocampal slices maintained in culture for several; weeks on the characteristics of AMPA and NMDA receptors and on the properties of LTP. Treatment of cultured hippocampal slices with excitotoxin or beta- amyloid peptide (betaAP) produces selective neuronal damage which exhibits several features of neuronal death occurring in AD. Specific Aims 3 and 4 will therefore evaluate the neuroprotective effects of estrogen in these models. Effects of estrogen in these in vitro systems will be compared with its effects in cultures of dissociated neurons as well as in in vivo models of synaptic plasticity and neurodegeneration.